Expanding thyroid testing in high risk newborns: total T3, free T4, TSH and TRAB

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ABSTRACT Thyroid dysfunction is among the most common morbidities of the neonatal period and can result in permanent cognitive disability and other serious complications if not rapidly identified and treated. While newborn thyroid screening in state public health laboratories has revolutionized the identification of children with severe congenital primary hypothyroidism, this screening does not effectively identify several other common neonatal disorders of thyroid function that may result from preterm birth or maternal hyperthyroidism. Major barriers to comprehensive thyroid testing in newborns currently include the relatively large volume of blood needed for multiple tests (>2 mL), long assay turn-around times and a need for repeated testing to establish an appropriate treatment plan. These limitations are further complicated by the lack of clear consensus guidelines for identification and treatment of hypothyroidism in preterm newborns. We propose to develop a novel digital microfluidic system (FINDER) for rapid, near patient thyroid testing in newborns using microliter volumes of whole blood. Through this Fast-Track SBIR mechanism, we will develop a multiplexed panel of assays to measure total T3, free T4, thyroid stimulating hormone (TSH) and thyrotropin receptor antibody (TRAB) in whole blood, with an anticipated run time of less than 45 minutes. The FINDER thyroid system will allow clinicians: to (a) rapidly identify infants with true central or primary hypothyroidism; (b) differentiate central hypothyroidism (which requires treatment) from the more common hypothyroxinemia of prematurity; (c) perform repeated thyroid function testing in blood volume-limited neonates; and (d) rapidly identify neonates with Graves disease as a consequence of maternal hyperthyroidism. Phase I Specific Aims include: 1) develop automated immunoassays for T3, free T4, TSH and TRAB on the digital microfluidic cartridge; 2) perform preliminary analytical validations of each assay; and 3) demonstrate preliminary feasibility of the individual assays on discarded serum samples. The key milestone for progression to Phase II will be the successful completion of all assays on-cartridge with high reliability and precision. Phase II Specific Aims are: 1) optimize reagent formulations for on-cartridge drying and storage; 2) multiplex all assays to perform simultaneously on the same cartridge using whole blood samples and perform analytical validations using dried reagents and whole blood samples; and 3) preliminary clinical validation of the complete thyroid testing panel using standard reference tests at Duke Clinical Laboratory as a comparison. At the conclusion of Phase II, we will have a commercializable product for rapid, efficient and accurate thyroid testing in high-risk newborns using microliter volumes of whole blood. We will seek FDA approval of the final product, which will initially be marketed for use in pediatric patients in U.S. hospitals, with a potential future market towards other patients who may benefit from the innovative features of the platform.